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Materials: Between Oct 1996 and Sept 1997, 576 recipients of primary mismatched kidney transplants in Australia, Canada, Europe and the United States were randomly allocated to have either 2 or 5 mg/d of rapamycin (RAPA), or placebo added to concentration controlled daily cyclosporine and protocol mandated steroid regimen in a ratio of 2:2:1 or 227:219:130 patients respectively. The primary end point was a composite of patient and graft loss, and incidence of biopsy confirmed acute rejection. Secondary end points included the incidence and severity of adverse events, the need for antibody rescue therapy and the incidence of withdrawal from protocol.
Results: By intention to treat analysis the one year patient survival was 97% in the 2 mg RAPA group, 95.2% in the 5 mg group and 94.7% with placebo (p=N.S.) and graft survival was 90% with 2 mg, 91.5% with 5 mg and 88% with placebo (p=N.S.). Biopsy confirmed acute rejection incidence was 19% (44/227) with 2 mg/d RAPA, 11% (24/219) with 5 mg, and 29% (38/130) with placebo (p=0.076, p=0.001 respectively). Withdrawals from protocol were higher in the placebo groups than in either RAPA group (55.4% vs 39.6% and 43.4% p=0.011 and P=0.033 at 6 mos). The severity of rejection episodes and the need for antibody rescue were both statistically significantly higher in the placebo groups than with either RAPA dose. The incidence of severe side effects including infections and PTLD did not differ except for lipidemias which occurred more frequently with RAPA. Protocol biopsies were done in the majority of patients at 1 year. These results are presently being analysed.
Conclusion: The addition of rapamycin to base therapy with cyclosporin and prednisone significantly reduces the frequency and severity of rejection episodes without an increase in overall adverse events and with a trend towards improved graft and patient survival.
